Phenyl-piperazine derivatives as serotonin reuptake inhibitors

ABSTRACT

The invention provides compounds represented by the general formula I  
                 
wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of prior application Ser. No. 10/488,280,which is a 371 National Stage application of PCT/DK02/00659, filed Oct.2, 2002. The prior application is hereby incorporated by reference inits entirety.

The present invention relates to novel compounds which are serotoninreuptake inhibitors and as such effective in the treatment of forexample depression and anxiety.

BACKGROUND OF THE INVENTION

Selective serotonin reuptake inhibitors (hereinafter referred to asSSRIs) have become first choice therapeutics in the treatment ofdepression, certain forms of anxiety and social phobias, because theyare effective, well tolerated and have a favourable safety profilecompared to the classic tricyclic antidepressants.

However, clinical studies on depression indicate that non-response toSSRIs is substantial, up to 30%. Another, often neglected, factor inantidepressant treatment is compliance, which has a rather profoundeffect on the patient's motivation to continue pharmacotherapy.

First of all, there is the delay in therapeutic effect of SSRIs.Sometimes symptoms even worsen during the first weeks of treatment.Secondly, sexual dysfunction is a side effect common to all SSRIs.Without addressing these problems, real progress in the pharmacotherapyof depression and anxiety disorders is not likely to happen.

In order to cope with non-response, psychiatrists sometimes make use ofaugmentation strategies. Augmentation of antidepressant therapy may beaccomplished through the co-administration of mood stabilizers such aslithium carbonate or triiodothyronin or by the use of electroshock.

The effect of combined administration of a compound that inhibitsserotonin reuptake and a 5-HT_(1A) receptor antagonist has beenevaluated in several studies (Innis et al. Eur. J. Pharmacol. 1987, 143,1095-204 and Gartside Br. J. Pharmacol. 1995, 115, 1064-1070, Blier etal. Trends in Pharmacol. Science 1994, 15, 220). In these studies, itwas found that 5-HT_(1A) receptor antagonists would abolish the initialbrake on 5-HT neurotransmission induced by the serotonin reuptakeinhibitors and thus produce an immediate boost of 5-HT transmission anda rapid onset of therapeutic action.

Several patent applications have been filed, which cover the use of acombination of a 5-HT_(1A) antagonist and a serotonin reuptake inhibitorfor the treatment of depression (see e.g. EP-A2-687472 andEP-A2-714663).

Another approach to increase terminal 5-HT would be through blockade ofthe 5-HT_(1B) autoreceptor. Microdialysis experiments in rats haveindeed shown that increase of hippocampal 5-HT by citalopram ispotentiated by GMC 2-29, an experimental 5-HT_(1B) receptor antagonist.

Several patent applications covering the combination of an SSRI and a5-HT_(1B) antagonist or partial agonist have also been filed (WO97/28141, WO 96/03400, EP-A-701819 and WO 99/13877).

It has previously been found that the combination of a serotoninreuptake inhibitor with a compound having 5-HT_(2C) antagonistic orinverse agonistic effect (compounds having a negative efficacy at the5-HT_(2C) receptor) provides a considerable increase in the level of5-HT in terminal areas, as measured in microdialysis experiments (WO01/41701). This would imply a shorter onset of antidepressant effect inthe clinic and an augmentation or potentiation of the therapeutic effectof the serotonin reuptake inhibitor (SRI).

The present invention provides compounds which are serotonin reuptakeinhibitors for the treatment of affective disorders such as depression,anxiety disorders including general anxiety disorder and panic disorderand obsessive compulsive disorder. Some of the compounds also have acombined effect of serotonin reuptake inhibition and 5-HT_(2c) receptormodulation, which according to WO01/41701 would imply a faster onset ofanti-depressant activity.

A few of the compounds embraced by the present invention have previouslybeen described in WO 01/49681 and in WO02/59108. However, the compoundsof WO01/49681 are not disclosed as having any therapeutic or biologicalactivity. The compounds of WO02/59108 are disclosed as intermediates inthe synthesis of compounds different from the compounds of the presentinvention with a terapeutic activity as melanocortin receptor agonists.One compound, 1-(2-phenoxyphenyl)-piperazine, embraced by the presentinvention, is disclosed in U.S. Pat. No. 4,064,245 as being useful inthe treatment of metabolic disorders.

SUMMARY OF THE INVENTION

The present invention provides compounds of the general formula I

wherein

Y is N, C or CH;

X represent O or S;

m is 1 or 2;

p is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

q is 0, 1, 2, 3 or 4;

s is 0, 1, 2, 3, 4 or 5;

The dotted line represents an optional bond;

Each R¹ is independently selected from the group represented byC₁₋₆-alkyl, or two R¹ attached to the same carbon atom may form a3-6-membered spiro-attached cyclo-alkyl;

Each R² is independently selected from the groups represented byhalogen, cyano, nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy,C₁₋₆-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,C₁₋₆-alk(en/yn)yloxycarbonyl, C₁₋₆-alk(en/yn)ylsulfonyl, or—NR^(x)R^(y);

Each R³ is independently selected from a group represented by halogen,cyano, nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy,C₁₋₆-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)ylsulfonyl, aryl,C₁₋₆-alk(en/yn)yloxycarbonyl, acyl, —NR^(x)CO—C₁₋₆-alk(en/yn)yl,CONR^(x)R^(y) or NR^(x)R^(y);

or two adjacent R³ substituents together form a heterocycle fused to thephenyl ring selected from the group consisting of

wherein W is O or S, and R′ and R″ are hydrogen or C₁₋₆-alkyl:

or two adjacent R³ substituents together form a fused heteroaromaticsystem containing one, two or three heteroatoms,

wherein each R^(x) and R^(y) is independently selected from the grouprepresented by hydrogen, C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, or aryl; or R^(x) and R^(y)together with the nitrogen to which they are attached form a3-7-membered ring which optionally contains one further heteroatom;

or an acid addition salt thereof.

The invention also provides compounds as above provided that thecompound is not 1-(2-phenoxyphenyl)-piperazine;

The invention also provides compounds as above provided that thecompound is not 1-[2-(2-Methoxyphenoxy)phenyl]piperazine,1-[2-(2,6-dimethoxyphenoxy)phenyl]-[1,4]-diazepane,1-{2-[3-(dimethylamino)phenoxy]phenyl}piperazine,1-[2-(4-methylphenoxy)phenyl]piperazine,1-[2-(3-methylphenoxy)phenyl]piperazine,1-[2-(3-chlorophenoxy)phenyl]piperazine,1-[2-(3-methoxyphenoxy)phenyl]piperazine and1-(2-phenoxyphenyl)-piperazine;

The invention provides a compound according to the above for use as amedicament.

The invention provides a pharmaceutical composition comprising acompound according to the above or a pharmaceutically acceptable acidaddition salt thereof and at least one pharmaceutically acceptablecarrier or diluent.

The invention provides the use of a compound according to the above or apharmaceutically acceptable acid addition salt thereof for thepreparation of a medicament for the treatment of affective disorders,such as depression, anxiety disorders including general anxiety disorderand panic disorder and obsessive compulsive disorder.

The invention provides a method for the treatment of an affectivedisorder, including depression, anxiety disorders including generalanxiety disorder and panic disorder and obsessive compulsive disorder ina living animal body, including a human, comprising administering atherapeutically effective amount of a compound according to the above ora pharmaceutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the invention are wherein p is 0;

Preferred embodiments of the invention are wherein m is 1 or 2;

Preferred embodiments of the invention are R² is trifluoromethyl, orC₁₋₆-alkyl;

Preferred embodiments of the invention are wherein R³ is selected fromthe group consisting of halogen, C₁₋₆-alkoxy, C₁₋₆-sulfanyl, C₁₋₆-alkyl,hydroxy or trifluoromethyl;

Particularly preferred embodiments of the invention are wherein thecompound of the invention is any of the following:

-   1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine,-   1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine,-   1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine,-   1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine,-   1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine,-   1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine,-   1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine,-   1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine,-   1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl][1,4]diazepane,-   1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane,-   1-[2-(4-Butylphenoxy)phenyl]piperazine,-   1-[2-(4-Methoxyphenoxy)phenyl]piperazine,-   2-(4-Methylphenylsulfanyl)phenyl-1-piperazine,-   1-[2-(4-Chlorophenylsulfanyl)phenyl]-piperazine,-   1-[2-(4-Methoxyphenylsulfanyl)-4-chlorophenyl]piperazine,-   1-[2-(4-Methoxyphenylsulfanyl)-4-methylphenyl]piperazine,-   1-[2-(4-Methoxyphenylsulfanyl)-5-methylphenyl]piperazine,-   1-[2-(4-Fluorophenylsulfanyl)-5-methylphenyl]piperazine,-   1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine,-   1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine,-   1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine,-   4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine,-   4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine or-   4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine    or a pharmaceutically acceptable acid addition salt thereof.

DEFINITION OF SUBSTITUENTS

Halogen means fluoro, chloro, bromo or iodo.

The expression C₁₋₆-alk(en/yn)yl means a C₁₋₆-alkyl, C₂₋₆-alkenyl or aC₂₋₆-alynyl group. The expression C₃₋₈-cycloalk(en)yl means aC₃₋₈-cycloalkyl- or cycloalkenyl group.

The term C₁₋₆ alkyl refers to a branched or unbranched alkyl grouphaving from one to six carbon atoms inclusive, including but not limitedto methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl and 2-methyl-1-propyl.

Similarly, C₂₋₆ alkenyl and C₂₋₆ alkynyl, respectively, designate suchgroups having from two to six carbon atoms, including one double bondand one triple bond respectively, including but not limited to ethenyl,propenyl, butenyl, ethynyl, propynyl and butynyl.

The term C₃₋₈ cycloalkyl designates a monocyclic or bicyclic carbocyclehaving three to eight C-atoms, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, etc.

The term C₃₋₈ cycloalkenyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms and including one double bond.

In the term C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yland C₁₋₆-alk(en)yn)yl are as defined above.

The terms C₁₋₆-alk(en/yn)yloxy, C₁₋₆ alk(en/yn)ylsulfanyl,hydroxy-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylsulfonyl etc. designate suchgroups in which the C₁₋₆-alk(en/yn)yl are as defined above.

As used herein, the term C₁₋₆-alk(en/yn)yloxycarbonyl refers to groupsof the formula C₁₋₆-alk(en/yn)yl-O—CO—, wherein C₁₋₆-alk(en/yn)yl are asdefined above.

As used herein, the term acyl refers to formyl,C₁₋₆-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C₁₋₆-alk(en/yn)ylcarbonyl,C₃₋₈-cycloalk(en)ylcarbonyl or aC₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl-carbonyl group.

The term 3-7-membered ring optionally containing one further heteroatomas used herein refers to ring systems such as 1-morpholinyl,1-piperidinyl, 1-azepinyl, 1-piperazinyl, 1-homopiperazinyl,1-imidazolyl, 1-pyrrolyl or pyrazolyl, all of which may be furthersubstituted with C₁₋₆-alkyl.

The heterocycles formed by two adjacent R³ substituents and fused to theparent ring may together form rings such as 5-membered monocyclic ringssuch as 3H-1,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole,3H-1,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole,1,2,3-thiadiazole, 1H-1,2,3-triazole, isoxazole, oxazole, isothiazole,thiazole, 1H-imidazole, 1H-pyrazole, 1H-pyrrole, furan or thiophene and6-membered monocyclic rings such as 1,2,3-oxathiazine,1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine,1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4H-1,3,2-dioxazine,1,4,2-dioxazine, 2H-1,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine,4H-1,3,2-dithiazine, 1,4,2-dithiazine, 2H-1,5,2-dithiazine,2H-1,2,3-oxadiazine, 2H-1,2,4-oxadiazine, 2H-1,2,5-oxadiazine,2H-1,2,6-oxadiazine, 2H-1,3,4-oxadiazine, 2H-1,2,3-thiadiazine,2H-1,2,4-thiadiazine, 2H-1,2,5-thiadiazine, 2H-1,2,6-thiadiazine,2H-1,3,4-thiadiazine, 1,2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine,2H-1,3-oxazine, 2H-1,4-oxazine, 2H-1,2-thiazine, 2H-1,3-thiazine,2H-1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-1,3-oxathiin,1,4-oxathiin, 4H-1,3-dioxin, 1,4-dioxin, 4H-1,3-dithiin, 1,4-dithiin,pyridine, 2H-pyran or 2H-thiin.

The term aryl refers to carbocyclic, aromatic systems such as phenyl andnaphtyl.

The acid addition salts of the invention are preferably pharmaceuticallyacceptable salts of the compounds of the invention formed with non-toxicacids. Exemplary of such organic salts are those with maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids,as well as the 8-halotheophyllines, for example 8-bromotheophylline.Exemplary of such inorganic salts are those with hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Some of the compounds of the present invention contain chiral centresand such compounds exist in the form of isomers (i.e. enantiomers). Theinvention includes all such isomers and any mixtures thereof includingracemic mixtures.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canalso be resolved into their optical antipodes, e.g. by fractionalcrystallization of d- or 1-(tartrates, mandelates or camphorsulphonate)salts. The compounds of the present invention may also be resolved bythe formation of diastereomeric derivatives.

Additional methods for the resolution of optical isomers, known to thoseskilled in the art, may be used. Such methods include those discussed byJ. Jaques, A. Collet and S. Wilen in “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically activestarting materials.

Pharmaceutical Compositions

The pharmaceutical formulations of the invention may be prepared byconventional methods in the art. For example: Tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvants or additives usually used for such purposessuch as colourings, flavourings, preservatives etc. may be used providedthat they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilising the solution and filling it in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

The pharmaceutical compositions of this invention or those which aremanufactured in accordance with this invention may be administered byany suitable route, for example orally in the form of tablets, capsules,powders, syrups, etc., or parenterally in the form of solutions forinjection. For preparing such compositions, methods well known in theart may be used, and any pharmaceutically acceptable carriers, diluents,excipients or other additives normally used in the art may be used.

Conveniently, the compounds of the invention are administered in unitdosage form containing said compounds in an amount of about 0.01 to 100mg. The total daily dose is usually in the range of about 0.05-500 mg,and most preferably about 0.1 to 50 mg of the active compound of theinvention.

The compounds of the invention are prepared by the following generalmethods:

a) Deprotection or cleavage from a polymer support of a compound withformula II

wherein Z represents

and R¹, R², R³, m, p, q, s, X, Y and the dotted line are as describedabove, and R′″ is a tert-butyl, methyl, ethyl, allyl or benzyl group orR′″OCO₂ is a solid supported carbamate group, such as the Wangresin-based carbamate linker.

b) Chemical transformation of a compound with formula III

wherein R¹, R², m, p, q, Y and the dotted line are as described above,to the corresponding diazonium compound, and subsequently reacting witha compound HXZ, wherein X and Z are as defined above.

c) Reacting a compound with formula IV

wherein R², R³, X, s and q are as described above with an alkylatingagent of formula (Cl—(CH₂)_(m+1))NH(CH₂)₂Cl or(Br—(CH₂)_(m+1))NH(CH₂)₂Br wherein m are as defined above.

d) Reacting a compound with formula V

wherein R², R³, X, s and q are as described above and G is a bromine oriodine atom with a compound of formula VI

wherein R¹, m and p are as defined above.

e) Dehydrating and optionally simultaneously deprotecting a compound offormula VII

wherein R¹, R², R³, X, m, p, q and s are as described above and R iseither a hydrogen atom or a BOC group.

f) Hydrogenate the double bond in a compound of formula VIII

wherein R¹, R², R³, X, m, p, q and s are as described above.

The deprotection according to method a) was performed by standardtechniques, known to the persons skilled in the art and detailed in thetextbook Protective Groups in Organic Synthesis T. W. Greene and P. G.M. Wuts, Wiley Interscience, (1991) ISBN 0471623016.

Starting materials of formula II wherein R′″=tert-Bu were preparedaccording to the procedure as outlined below. Fluoronitrobenzenederivatives were reacted with phenols or thiophenols according to theprocedure of Sawyer et al. J. Org. Chem. 1998, 63, 6338 followed byreduction using standard procedures known to the persons skilled in theart.

This includes reduction to the corresponding aniline using a metalhydride salt such as sodium borohydride in conjunction with palladium oncarbon catalyst in an alcoholic solvent or reduction using a metalchloride salt such as zinc chloride or tin chloride. The resultinganiline was then converted to a properly substituted3,5-diketopiperazine in a modification of the procedure of Kruse et al.Recl. Trav. Chim. Pays-Bas 1998, 107, 303 usingN-butyloxycarbonyliminodiacetic acid. The 3,5-diketopiperazinederivative was then reduced with for example borane to the correspondingBOC protected piperazine, which was then deprotected to the piperazinein situ.

The compounds shown in formula II, wherein Y═CH and the optional doublebond is reduced, were prepared from their tertiary alcohol precursorsVII wherein R is a BOC group, by a modified Barton reduction in asimilar manner as described in Hansen et al. Synthesis 1999, 1925-1930.The intermediate tertiary alcohols were prepared from the correspondingproperly substituted 1-bromo-phenylsulfanylbenzenes or theircorresponding ethers by metal-halogen exchange followed by addition ofan appropriate electrophile of the formula IX in a similar manner asdescribed in Palmer et al. J. Med. Chem. 1997, 40, 1982-1989. Theproperly substituted 1-bromo-phenylsulfanylbenzenes were prepared in asimilar manner as described in the literature by reaction of properlysubstituted thiophenols with properly substituted aryliodides accordingto Schopfer and Schlapbach Tetrahedron 2001, 57, 3069-3073 Bates et al.,Org. Lett. 2002, 4, 2803-2806 and Kwong et al. Org. Lett. 2002, 4, (inpress). The corresponding substituted 1-bromo-phenoxybenzenes may beprepared as described by Buck et al. Org. Lett. 2002, 4, 1623-1626.

The cleavage from a polymer support, such as from the Wang resin basedcarbamate linker, according to method a) was performed according toliterature known procedures (Zaragoza Tetrahedron Lett. 1995, 36,8677-8678 and Conti et al. Tetrahedron Lett. 1997, 38, 2915-2918).

The starting material of formula II may also be prepared according tothe methods described in patent application WO 01/49681. The diamineswere either commercially available or synthesised by methods known tochemists skilled in the art. Iron-complexes, likeη⁶-1,2-dichlorobenzene-η⁵-cyclopentadienyliron(II) hexafluorophosphateand substituted analogues were synthesised according to literature knownprocedures (Pearson et al. J. Org. Chem. 1996, 61, 1297-1305) orsynthesised by methods known to chemists skilled in the art.

The diazotation followed by reaction with a compound HXZ according tothe method b) was performed by addition of the diazonium salt of thecorresponding aniline to a solution of sodium salt of a thiophenol or aphenol in an aqueous suspension of copper. The starting material offormula III was prepared as outlined in the following. Afluoronitrobenzene derivative was reacted with a piperazine derivativein a solvent such as DMF, NMP or other dipolar aprotic solventcontaining an organic base such as triethylamine to afford theorthonitophenylpiperazine derivative. The intermediateorthonitrophenylpiperazine was subsequently reduced using standardprocedures as stated above to give the starting material of formula III.

The reaction of a compound of formula IV with an alkylating agent offormula (Cl—(CH₂)_(m+1))NH(CH₂)₂Cl or (Br—(CH₂)_(m+1))NH(CH₂)₂Br as itshydrobromide or hydrochloride salt, wherein m is as defined above wasperformed in a similar manner as described in Sircar et al. J. Med.Chem. 1992, 35, 4442-4449. Starting materials of formula IV wereprepared as described above for starting materials of formula II.

The reaction of a compound of formula V with a diamine of formula VI inmethod d) was performed in a similar manner as described in Nishiyama etal. Tetrahedron Lett. 1998, 39, 617-620. The starting material offormula V was prepared in a similar manner as described in Schopfer etal. Tetrahedron 2001, 57, 3069-3073.

The dehydration reaction and optional simultaneous deprotection of acompound of formula VII in method e) was performed in a similar manneras described in Palmer et al J. Med. Chem. 1997, 40, 1982-1989. Thestarting material of formula VII wherein R═H was prepared from acompound of formula VII wherein R is a BOC group (see above) bydeprotection with hydrochloric acid in methanol. Compounds of formulaVII wherein R═BOC, may be prepared as described in Palmer et al. J. Med.Chem. 1997, 40, 1982-1989.

The reduction of the double bond according to method f) was generallyperformed by catalytic hydrogenation at low pressure (<3 atm.) in a Parrapparatus, or by using reducing agents such as diborane or hydroboricderivatives as produced in situ from NaBH₄ in trifluoroacetic acid ininert solvents such as tetrahydrofuran (THF), dioxane, or diethyl ether.The starting material of formula VIII was prepared from II as describedin method a).

EXAMPLES

Analytical LC-MS data were obtained on a PE Sciex API 150EX instrumentequipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system.Column: 30×4.6 mm Waters Symmmetry C18 column with 3.5 μm particle size;Solventsystem: A=water/trifluoroacetic acid (100:0.05) andB=water/acetonitrile/trifluoroacetic acid (5:95:0.03); Method: Lineargradient elution with 90% A to 100% B in 4 min and with a flow rate of 2mL/min. Purity was determined by integration of the UV (254 nm) and ELSDtrace. The retention times (RT) are expressed in minutes.

Preparative LC-MS-purification was performed on the same instrument.Column: 50×20 mm YMC ODS-A with 5 μm particle size; Method: Lineargradient elution with 80% A to 100% B in 7 min and with a flow rate of22.7 mL/min. Fraction collection was performed by split-flow MSdetection.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuteratedmethylenchloride (99.8% D), chloroform (99.8% D) or dimethyl sulfoxide(99.8% D) were used as solvents. TMS was used as internal referencestandard. Chemical shift values are expressed in ppm-values. Thefollowing abbreviations are used for multiplicity of NMR signals:s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet,dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet oftriplets, m=multiplet and b=broad singlet.

For ion-exchange chromatography, the following material was used:SCX-columns (1 g) from Varian Mega Bond Elut®, Chrompack cat. No.220776. Prior to use, the SCX-columns were pre-conditioned with 10%solution of acetic acid in methanol (3 mL). For de-complexation byirradiation, a ultaviolet light source (300 W) from Philipps was used.As starting polymer supports for solid phase synthesis, Wang-resin (1.03mmol/g, Rapp-Polymere, Tuebingen, Germany) was used.

Preparation of Intermediatesη⁶-1,2-Dichlorobenzene-η⁵-cyclopentadienyliron(II) hexafluorophosphate

Ferrocene (167 g), anhydrous aluminium trichloride (238 g) and powderedaluminium (24 g) were suspended in 1,2-dichlorobenzene (500 mL) andheated to 90° C. in a nitrogen atmosphere for 5 h with intensivestirring. The mixture was cooled to room temperature and water (1000 mL)was added carefully in small portions while cooling on an ice bath.Heptane (500 mL) and diethylether (500 mL) were added, and the mixturewas stirred at room temperature for 30 minutes. The mixture wasextracted with diethylether (3×300 mL). The aqueous phase was filtered,and aqueous ammonium hexafluorophosphate (60 g in 50 mL water) was addedin small portions under stirring. The product was allowed to precipitateat room temperature. After 3 hours the precipitate was filtered off,washed intensively with water and dried in vacuo (50 ° C.) to give 81 g(21%) of the title compound as a light yellow powder. ¹H NMR (D₆-DMSO):5.29 (s, 5H); 6.48 (m, 2H); 7.07 (m, 2H).

Preparation of Polystyrene-Bound Amines4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene

4-[(4-Nitrophenoxy)carbonyloxymethyl]phenoxymethyl polystyrene (267 g,235 mmol) was suspended in dry N,N-dimethylfonnamide (2 L).N-Methylmorpholine (238.0 g, 2.35 mol) and piperazine (102.0 g, 1.17mol) were added and the mixture was stirred at room temperature for 16h. The resin was filtered off and washed with N,N-dimethylformamide (2×1L), tetrahydrofuran (2×1 L), water (1×500 mL), methanol (2×1 L),tetrahydrofuran (2×1 L) and methanol (1×1 L). Finally, the resin waswashed with dichloromethane (3×500 mL) and dried in vacuo (25° C., 36 h)to yield an almost colourless resin (240.0 g).

The following polystyrene bound diamines were prepared analogously:

4-[(1,4-Diazepan-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene

Preparation of Resin-Bound η⁶-aryl-η⁵-cyclopentadienyliron(II)hexafluorophosphates4-({4-[η⁶-(2-Chlorophenyl)-η⁵-cyclopentadienyliron(II)]piperazin-1-yl}carbonyloxymethyl)phenoxymethylpolystyrene hexafluorophosphate (Intermediate for 1a-1h and 1k-1l)

4-[(Piperazin-1-yl)carbonyloxymethyl]phenoxymethyl polystyrene (115.1 g,92 mmol) was suspended in dry tetrahydrofuran (1.6 L), andη⁶-1,2-dichlorobenzene-η⁵-cyclopentadienyliron(II) hexafluorophosphate(76.0 g, 184 mmol) was added followed by potassium carbonate (50.9 g,368 mmol). The reaction mixture was stirred at 60° C. for 16 h. Aftercooling to room temperature, the resin was filtered off and washed withtetrahydrofuran (2×500 mL), water (2×250 mL), tetrahydrofuran (2×500mL), water (2×250 mL), methanol (2×250 mL), dichloromethane (2×250 mL)and methanol (2×250 mL). Finally, the resin was washed withdichloromethane (3×500 mL) and dried in vacuo (25° C., 36 h) to yield adark orange resin (142 g).

The following polystyrene bound iron-complex was prepared analogously:

4-({4-[η⁶-(2-Chloro-phenyl)-η⁵-cyclopentadienyliron(II)]-[1,4]-diazepan-1-yl}carbonyloxymethyl)phenoxymethylpolystyrene hexafluorophosphate (Intermediate for 1i and 1j) Preparationof Further Intermediates1-tert-Butoxycarbonyl-4-[2-(4-methylphenylsulanyl)phenyl]piperidin-4-ol

A solution of BuLi (2.5 M in hexane, 12.0 ml, 30 mmol) was slowly addedto a stirred solution of 1-bromo-2-(4-methylphenylsulfanyl)benzene (30mmol) in dry THF (75 ml) under Argon at −78° C. The solution was stirredfor 10 min before 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(5.98 g, 30 mmol) was added in one portion. The solution was allowed towarm up to room temperature and then stirred for 3 h. Saturated aqueousNH₄Cl (150 ml) was added and the solution was extracted withethylacetate (150 ml). The organic phase was washed with brine, dried(MgSO₄) and the solvent was evaporated in vacuo. Crude 1 was purified byflash chromatography on silica gel (eluent: Ethylacetat/heptane 20:80)to produce the target compound as a white foam. LC/MS (m/z) 399.3 (MH⁺);RT=3.82; purity (UV, ELSD): 98%, 100%; yield: 5.02 g (42%).

1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-dioxopiperazine(Intermediate for 2a)

2-(4-Methylphenylsulfanyl)aniline (2.9 g, 13.5 mmol) was dissolved indry THF (200 mL) and placed under a nitrogen atmosphere.N-(tert-butylocycarbonyl)iminodiacetic acid (4.7 g, 20.2 mmol) andcarbonyl diimidazole (4.2 g, 40.4 mmol) were added to the solution andthe reaction was refluxed for 60 hours. The reaction mixture was cooledto room temperature and ethyl acetate (500 mL) was added. The resultingsolution was then washed with 2 N NaHCO₃ (2×200 mL), 2 N HCl (2×200 mL)and saturated sodium chloride solution (100 mL) and the solventsevaporated in vacuo. Yield 6.0 g, 107%, ¹H NMR (CDCl₃) 1.5 (s, 9H); 2.32(s, 3H); 4.4-4.6 (m, 4H); 7.02-7.18 (m, 3H); 7.2-7.45 (m, 5H).

The following 3,5 diketopiperazine derivatives were prepared in ananalogous fashion:

-   1-tert-Butyloxycarbonyl-4-[2-(4-chlorophenylsulfanyl)phenyl]-3,5-dioxopiperazine    (Intermediate for 2b)-   1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-chlorophenyl]-3,5-dioxopiperazine    (Intermediate for 2c)-   1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]-3,5-dioxopiperazine    (Intermediate for 2d)-   1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]-3,5-dioxopiperazine    (Intermediate for 2e)-   1-tert-Butyloxycarbonyl-4-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]-3,5-dioxopiperazine    (Intermediate for 2f)-   1-tert-Butyloxycarbonyl-4-[2-(4-methoxyphenylsulfanyl)-5-trifluoromethylphenyl]-3,5-dioxopiperazine    (Intermediate for 2g)

2-(3-Methylpiperazin-1-yl)phenylamine (Intermediate for 3a)

Fluoronitrobenzene (7.1 g, 50 mmol) was dissolved in DMF (100 mL)containing triethylamine (10 g, 100 mmol) and placed under a nitrogenatmosphere. To the solution was added 2-methyl-piperazine (5.5 g, 55mmol). The reaction was heated to 80° C. for 16 hours. The reaction wasallowed to cool to room temperature before the solvent was reduced tohalf volume in vacuo. Ethyl acetate (200 mL) and ice-water (250 mL) wereadded to the solution and the product was extracted with diethyether(2×200 mL). The aqueous phase was saturated with sodium chloride andextracted with ethyl acetate (2×200 mL). The organic phases werecombined, washed with saturated brine, dried over magnesium sulfate,filtered and the filtrate was concentrated in vacuo. The product (10.5g) was dissolved in ethanol (250 mL). Palladium on charcoal catalyst(10% w/w, 2.2 g) was added to the solution and the solution washydrogenated in a Parr apparatus at 3 bar for 3 hours. The solution wasfiltered and the solvents evaporated in vacuo to give the anilineproduct. Yield (8.0 g, 83%)

The following intermediates were prepared in an analogous fashion:

2-(3,5-Dimethylpiperazin-1-yl)phenylamine (Intermediatefor 3b)

Compounds of the Invention Example 1 1a,1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]piperazine

To a solution of 2-trifluoromethylthiophenol (1.75 g, 9.8 mmol) in a 1:1mixture of tetrahydrofuran/dimethylformamide (30 mL), sodium hydride(7.4 mmol, 60% in mineral oil) was carefully added at room temperature(Caution: Generation of hydrogen). The mixture was stirred for anadditional 30 min after the generation of hydrogen had ceased.Subsequently,4-({4-[η⁶-(2-chloro-phenyl)-η⁵-cyclopentadienyliron(II)]piperazin-1-yl}carbonyloxymethyl)phenoxymethylpolystyrene hexafluorophosphate (3.5 g, 2.45 mmol) was added and themixture was stirred at 55° C. for 12 h. After cooling to roomtemperature, the resin was filtered off and washed with tetrahydrofuran(2×50 mL), tetrahydrofuran/water (1:1) (2×50 mL), N,N-dimethylformamide(2×50 mL), water (2×50 mL), methanol (3×50 mL), tetrahydrofuran (3×50mL), and subsequently with methanol and tetrahydrofuran (each 50 mL, 5cycles). Finally, the resin was washed with dichloromethane (3×50 mL)and dried in vacuo (25° C., 12 h) to yield a dark orange resin. The thusobtained resin and a 0.5 M solution of 1,10-phenanthroline in 3:1mixture of pyridine/water (20 mL) was placed in light-transparentreactor tube. The suspension was agitated by rotation under irradiationwith visible light for 12 h. The resin was filtered and washed withmethanol (2×25 mL), water (2×25 mL) and tetrahydrofuran (3×25 mL) untilthe washing solutions were colourless (approx. 5 cycles) and theirradiation procedure was repeated until decomplexation was complete(approx. 5 cycles). After the decomplexation was completed, the resinwas washed with dichlormethane (3×25 mL) and dried in vacuo (25° C., 12h) to obtain a light brown resin. 100 mg (77 μmol) of the thus obtainedresin were suspended in a 1:1 mixture of trifluoroacetic acid anddichlormethane (2 mL) and stirred at room temperature for 2 h. The resinwas filtered off and washed with methanol (1×0.5 mL) and dichloromethane(1×0.5 mL). The filtrates were collected and the volatile solventsevaporated in vacuo. The crude product was purified by preparative LC-MSand subsequently by ion-exchange chromatography. LC/MS (m/z) 339 (MH⁺);RT=2.39; purity (UV, ELSD): 92%, 100%; overall yield: 1 mg (4%).

The following arylpiperazines and aryl[1,4]diazepanes were preparedanalogously:

-   1b, 1-[2-(4-Bromophenylsulfanyl)phenyl]piperazine: LC/MS (m/z) 350    (MH⁺); RT=2.46; purity (UV, ELSD): 75%, 92%; yield: 2 mg (7%).-   1c, 1-{2-[4-(Methylsulfanyl)phenylsulfanyl]phenyl}piperazine: LC/MS    (m/z) 317 (MH⁺); RT=2.39; purity (UV, ELSD): 91%, 100%; yield: 2 mg    (8%).-   1d, 1-[2-(4-Hydroxyphenylsulfanyl]phenyl}piperazine: LC/MS (m/z) 287    (MH⁺); RT=1.83; purity (UV, ELSD): 84%, 100%; yield: 3 mg (13%).-   1e, 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z)    299 (MH⁺); RT=2.48; purity (UV, ELSD): 95%, 100%; yield: 4 mg (17%).-   1f, 1-[2-(3,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z)    299 (MH⁺); RT=2.51; purity (UV, ELSD): 96%, 100%; yield: 5 mg (21%).-   1g, 1-[2-(2,6-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z)    299 (MH⁺); RT=2.42; purity (UV, ELSD): 97%, 100%; yield: 4 mg (17%).-   1h, 1-[2-(2,5-Dimethylphenylsulfanyl)phenyl]piperazine: LC/MS (m/z)    299 (MH⁺); RT=2.46; purity (UV, ELSD): 97%, 100%; yield: 1 mg (4%).-   1i, 1-[2-(2-Trifluoromethylphenylsulfanyl)phenyl]-[1,4]-diazepane:    LC/MS (m/z) 353 (MH⁺); RT=2.46; purity (UV, ELSD): 70%, 96%; yield:    1 mg (4%).-   1j, 1-[2-(3-Methylphenylsulfanyl)phenyl]-[1,4]-diazepane: LC/MS    (m/z) 299 (MH⁺); RT=2.44; purity (UV, ELSD): 76%, 93%; yield: 1 mg    (4%).-   1k, 1-[2-(4-Butylphenoxy)phenyl]piperazine: LC/MS (m/z) 311 (MH⁺);    RT=2.77; purity (UV, ELSD): 91%, 100%; yield: 4 mg (17%).-   1l, 1-[2-(4-Methoxyphenoxy)phenyl]piperazine: LC/MS (m/z) 285 (MH⁺);    RT=2.08; purity (UV, ELSD): 93%, 100%; yield: 4 mg (18%)

Example 2 2a, 2-(4-Methylphenylsulfanyl)phenyl-1-piperazinehydrochloride

1-tert-Butyloxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]-3,5-dioxo-piperazine(5.5 g, 13 mmol) was dissolved in dry THF (50 mL) and placed under anitrogen atmosphere. Borane tetrahydrofuran complex (50 mmol, 1.0 M) intetrahydrofuran was added and the reaction was refluxed for ten minutes.Excess borane was quenched by the addition of an excess of ethyl acetateand the reaction was refluxed for a further 20 minutes. The reaction wasallowed to cool to room temperature before hydrogen chloride dissolvedin methanol (50 mL, 4 M) was added and the reaction was refluxed for 4.5hours. The reaction was allowed to cool to room temperature and thereaction was concentrated in vacuo. The compound was crystallised fromthe gum residue by the addition of ether/methanol solution. Thecrystalline solid was filtered and washed with ether/methanol (1:1) togive a white crystalline solid. Yield (2.0 g, 47%) ¹H NMR (D₆-DMSO) 2.35(s, 3H); 3.18 (br s, 8H); 6.68 (d, 2H); 7.02 (m, 1H); 7.18 (m, 1H);7.3-7.5 (m, 4H); MS (MH⁺) 285.

The following compounds were prepared in an analogous fashion:

-   2b, 1-[2-(4-chlorophenylsulfanyl)phenyl]piperazine LC-MS (m/z) 305.1    (MH⁺) RT=2.46 purity (UV, ELSD) 71%, 91% yield 0.096 g, 100%-   2c, 1-[2-(4-methoxyphenysulfsanyl)-4-chlorophenyl]piperazine LC-MS    (m/z) (MH⁺) 335.2 RT=2.38 purity (UV, ELSD) 98%, 100% yield 0.22 g,    62%-   2d, 1-[2-(4-methoxyphenylsulfanyl)-4-methylphenyl]piperazine LC-MS    (m/z) (MH⁺) 315.1 RT=2.33 purity (UV, ELSD) 97%,100% yield 0.21 g,    56%-   2e, 1-[2-(4-methoxyphenylsulfanyl)-5-methylphenyl]piperazine LC-MS    (m/z) (MH⁺) 315.2 RT=2.38 (UV, ELSD)98%,100% yield 2.3 g, 58%-   2f, 1-[2-(4-fluorophenylsulfanyl)-5-methylphenyl]piperazine LC-MS    (m/z) (MH⁺) 303.2 RT=2.46 (UV) 98% yield 2.1 g, 62%-   2g,    1-[2-(4-Methoxyphenylsulfanyl)-5-trifluoromethylphenyl]piperazine    LC-MS (m/z) (MH⁺) 369 RT=2.50 (UV, ELSD) 96%, 100% yield 0.54 g, 31%

Example 3 3a, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3-methylpiperazine

2-(3-Methylpiperazin-1-yl)phenylamine (0.96 g, 5 mmol) was dissolved in30 mL water containing sulfuric acid (0.28 mL, 5.2 mmol) and thesolution was cooled to 0° C. and sodium nitrite (0.36 g, 5.2 mmol) wasadded. The reaction was stirred for 30 minutes before the pH of thereaction was adjusted to pH 7 with sodium acetate. The diazonium saltsolution was then added dropwise to a solution of 4-chlorothiophenol ina suspension of copper (0.3 g, 5 mmol) in 2 M NaOH (4 mL). Afteraddition, the reaction mixture was heated to 60° C. for 30 minutesbefore being allowed to cool to room temperature and ethyl acetate (10mL) was added. The reaction mixture was filtered and the layers wereseparated. The aqueous layer was extracted with ethyl acetate (2×10 mL).The combined organic phases were dried (MgSO₄) and volatile solventsevaporated in vacuo. The crude product was purified by flashchromatography using silica gel, eluting with ethylacetate/methanol/ammonia 96:3:1. The pure product was isolated as acolourless oil. Yield (0.18 g , 11%) ¹H NMR (CDCl₃, 500 MHz) 1.12 (d,3H); 2.6-2.72 (br m, 2H); 3.0-3.15 (m, 5H); 6.9 (m, 2H); 7.08 (d, 1H);7.15 (m, 1H); 7.25-7.35 (m, 4H); MS (MH⁺) 319.1.

The following compound was prepared in an analogous fashion:

3b, 1-[2-(4-Chlorophenylsulfanyl)phenyl]-3,5-dimethylpiperazine LC-MS(m/z) (MH)+333.1 RT=2.29 (UV, ELSD) 83%, 100% yield 0.54 g, 31%.

Example 4 4a,4-[2-(4-Methylphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine

Concentrated aq hydrochloric acid (10 ml) was added to a stirredsolution of1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol(0.84 g, 2.1 mmol) in acetic acid (30 mL). The solution was boiled underreflux overnight, cooled to room temperature and then stirred in an icebath. An aqueous solution of NaOH (9.1 M, 40 mL) was slowly added andthe unclear solution was extracted with ethyl acetate (2×40 ml). Thecombined organic phases were dried (MgSO₄) and the solvents evaporatedin vacuo. The crude material (0.48 g) was dissolved in ethyl acetate(3.2 mL) at 50° C. and a solution of oxalic acid (0.11 g) in EtOH (3.2mL) was slowly added. The target compound was collected as a whiteoxalic salt. ¹H (DMSO-d₆) δ 7.3-7.2 (m, 7H); 7.15 (m, 1H); 7.00 (m, 1H);5.6 (d, 1H); 3.7 (d, 2H); 3.25 (t, 2H); 2.6 (m, 2H); 2.3 (s, 3H).

LC/MS (m/z) 282.2 (MH⁺); RT=2.24; purity (UV, ELSD): 99%, 100%; yield:0.31 g (40%).

The following derivative was prepared analogously:

4b, 4-[2-(4-Methoxyphenylsulfanyl)phenyl]-3,6-dihydro-2H-pyridine

LC/MS (m/z) 298 (MH⁺); RT=2.00; purity (UV, ELSD): 97%, 100%; yield:0.28 g (30%).

Example 5 5a, 4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine

Methyl Chloro-oxo-acetate (1.37 g, 11.25 mmol) was added to a stirredsolution of1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol(3.00 g, 7.5 mmol) and 4-(dimethylamino)pyridine (1.65 g, 13.5 mmol) ina mixture of dry CH₃CN (24 ml) and CHCl₃ (12 mL) at 0° C. under argon.The reaction mixture was allowed to reach room temperature and thenstirred 2 h. Ethyl acetate (140 mL) was added and some salts wereremoved by filtration through celite. The organic phase was washed withsat. NaHCO₃ (140 ml), brine (140 mL) and dried (MgSO₄). The solventswere evaporated in vacuo and the crude material was dried in vacuo. Thismaterial was dissolved in dry toluen (48 mL) under argon. Bu₃SnH (3.27g, 11.25 mmol) and AIBN (0.31 g, 1.88 mmol) were added. The solution wasstirred under argon at 90° C. for 2.5 h. The solvent was evaporated invacuo, and the crude material was purified by flash chromatography onsilicagel (eluent: a stepwise gradient of ethylacetat in heptane from10:90 to 20:80) to produce4-(2-(4-methylphenylsulfanyl)phenyl)-piperidine-1-carboxylic acidtert-butyl ester as a clear oil (1.94 g, 67%). This oil was dissolved inMeOH (9.2 mL) and HCl in diethylether (2.0 M) was added at 0° C. Thereaction mixture was allowed to warm to room temperature and stirredovernight. The target compound was collected as its hydrochloride. M.p229-231° C. Calculated for C₁₈H₂₁NS.HCl: C, 67.58; H, 6.63; N, 4.38.Found: C, 67.33; H, 6.97; N, 4.31. LC/MS (m/z) 284 (MH⁺); RT=2.12;purity (UV, ELSD): 96%, 100%; yield: 0.26 g (46%).

Inhibition of the Uptake of [³H]Serotonin into Whole Rat BrainSynaptosomes

The compounds were tested with respect to their 5-HT reuptake inhibitingeffect by measuring their ability to inhibit the uptake of [³H]serotonininto whole rat brain synaptosomes in vitro. The assay was performed asdescribed by Hyttel Psychopharmacology 1978, 60, 13.

5-HT_(2C) Receptor Efficacy as Determined by Fluorometry

The compounds were tested with respect to their efficacy on 5-HT_(2C)receptor-expressing CHO cells (Euroscreen) as determined by fluorometricimaging plate reader (FLIPR) analysis. This assay was carried outaccording to Molecular Devices Inc. instructions for their FLIPR CalciumAssay Kit and as modified from Porter et al. British Journal ofPharmacology 1999, 128, 13.

Preferred compounds of the present invention exhibit serotonin reuptakeinhibition below 200 nM (IC₅₀) in the assay above. More preferred arethe compounds which exhibit inhibition below 100 nM and most preferablybelow 50 nM. Compounds of particular interest exhibit serotonin reuptakeinhibition below 10 nM;

1. A compound represented by the general formula I

wherein X represents O or S; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; q is 0,1, 2, 3 or 4; s is 0, 1, 2, 3, 4 or 5; each R¹ is independently selectedfrom the group represented by C₁₋₆-alkyl, or two R¹ attached to the samecarbon atom may form a 3-6-membered spiro-attached cycloalkyl; each R²is independently selected from the groups represented by halogen, cyano,nitro, C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy,C₁₋₆-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, acyl,C₁₋₆-alk(en/yn)yloxycarbonyl, C₁₋₆-alk(en/yn)ylsulfonyl, or—NR^(x)R^(y); —NR^(x)CO—C₁₋₆-alk(en/yn)yl; each R³ is independentlyselected from a group represented by halogen, cyano, nitro,C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)yloxy, C₁₋₆-alk(en/yn)ylsulfanyl,hydroxy, hydroxy-C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl,halo-C₁₋₆-alk(en/yn)yloxy, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆-alk(en/yn)yl, C₁₋₆-alk(en/yn)ylsulfonyl, aryl,C₁₋₆-alk(en/yn)yloxycarbonyl, acyl, —NR^(x)CO—C₁₋₆-alk(en/yn)yl,—CONR^(x)R^(y) or NR^(x)R^(y); or two adjacent R³ substituents togetherform a heterocycle fused to the phenyl ring selected from the groupconsisting of

wherein W is O or S, and R′ and R″ are hydrogen or C₁₋₆-alkyl, or twoadjacent R³ substituents together form a fused heteroaromatic systemcontaining one, two or three heteroatoms, wherein each R^(x) and R^(y)is independently selected from the group represented by hydrogen,C₁₋₆-alk(en/yn)yl, C₃₋₈-cycloalk(en)yl,C₃₋₈-cycloalk(en)yl-C₁₋₆alk(en/yn)yl, or aryl; or R^(X) and R^(Y)together with the nitrogen to which they are attached form a3-7-membered ring which optionally contains one further heteroatom; or apharmaceutically acceptable acid addition salt thereof.
 2. (canceled) 3.(canceled)
 4. The compound according to claim 1, wherein p is 0, 1 or 2.5. The compound according to claim 1, wherein R¹ is C₁₋₆-alkyl. 6.(canceled)
 7. The compound according to claim 1, wherein q is 0, 1 or 2.8. The compound according to claim 1, wherein R² is trifluoromethyl, orC₁₋₆-alkyl.
 9. The compound according to claim 1, wherein s is 1 or 2.10. The compound according to claim 1, wherein R³ is selected from thegroup consisting of halogen, C₁₋₆-alkoxy, C₁₋₆-sulfanyl, C₁₋₆-alkyl,hydroxy or trifluoromethyl.
 11. The compound according to claim 1, saidcompound being 4-[2-(4-Methylphenylsulfanyl)phenyl]piperidine or apharmaceutically acceptable acid addition salt thereof.
 12. Apharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable acid addition salt thereof and at leastone pharmaceutically acceptable carrier or diluent.
 13. (canceled)
 14. Amethod for the treatment of an affective disorder, in a living animalbody, comprising administering a therapeutically effective amount of acompound according to claim 1 or a pharmaceutically acceptable acidaddition salt thereof.
 15. (canceled)
 16. The method of claim 14,wherein the living animal body is a human.
 17. The method of claim 14,wherein the affective disorder is selected from the group consisting ofdepression, anxiety disorder, and obsessive compulsive disorder.
 18. Themethod of claim 17, wherein the anxiety disorder is selected from thegroup consisting of general anxiety disorder and panic disorder.